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Document 1528694
A study of the pathology and pathogenesis of myocardial lesions in
gousiekte, a cardiotoxicosis of ruminants
CHAPTER 1
INTRODUCTION
Southern Africa is inherently rich in fauna and flora and has many poisonous
plants (Kellerman et al. 2005), as well as a large number of infectious diseases
(Coetzer & Tustin 2004). It is essential, from a diagnostic point of view, to
distinguish plant poisonings from other poisonings and from infectious diseases.
A sound knowledge of the economic impact of plant poisonings is important in
determining research priorities, evaluating risk and developing or implementing
cost-effective control measures (Kellerman, Naudé & Fourie 1995). The losses
incurred as a result of plant poisonings can be either direct or indirect. Direct
losses entail, amongst others, death, reduced milk yield and reproductive failure
(Nielsen & James 1992). Indirect losses include the cost of control measures,
for example fencing, strategic grazing practices, supplementary feeding,
veterinary expenses, and temporary or permanent non-utilisation of affected
pastures, and the diminished value of infested land.
Based on a model developed by Nielsen and James (1992), a study of the
economic impact of plant poisonings/mycotoxicoses on the livestock industry of
South Africa was conducted by Kellerman, Naudé and Fourie (1995). According
to this study the annual countrywide stock losses from all causes, including
drought, infectious diseases and internal parasites, were estimated at 3 % for
cattle and 5 % for small stock. In the case of cattle, 10 % of the total number of
deaths could be attributed to poisonous plants/mycotoxicoses. In the case of
small stock this figure was 15 %.
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A study of the pathology and pathogenesis of myocardial lesions in gousiekte, a cardiotoxicosis of ruminants
In 1995/96, cattle were valued at R1 531 a head and small stock at R177 a
head. Consequently, the estimated cost of plant poisonings/mycotoxicoses in
South Africa in 1995/96 was approximately R58 million in the case of cattle and
R47 million in the case small stock (Kellerman, Naudé & Fourie 1995). Based
on consultation with experienced veterinarians and/or stock owners, the current
(2008) mean values for cattle and small stock are taken as R6 000 and R1 000
a head, respectively (L. Prozesky, University of Pretoria, unpublished data
2008). Using the cattle and small stock numbers cited by Kellerman, Naudé and
Fourie (1995), the current total annual cost of plant poisonings/mycotoxicoses
to the livestock industry in South Africa amounts to approximately R226 million
in the case of cattle and R264 million in the case of small stock.
Sixty per cent of stock losses attributed to plant/mycotoxin poisonings were
ascribed to six poisonous plants and mycotoxicoses in both cattle and small
stock. The diseases in question are cardiac glycoside poisoning, caused by
Moraea spp. in particular, seneciosis, gifblaar poisoning (Dichapetalum
cymosum), gousiekte, Lantana poisoning (Lantana camara) and diplodiosis
(Diplodia maydis) in cattle, and geeldikkop (Tribulus terrestris) and dikoor,
vermeersiekte (Geigeria spp.), cardiac glycoside poisoning, seneciosis,
gousiekte and diplodiosis in small stock.
Gousiekte (direct translation “quick disease”) is a cardiotoxicosis of ruminants
characterised by heart failure four to eight weeks after the ingestion of certain
rubiaceous plants (Newsholme & Coetzer 1984; Kellerman et al. 2005). Animals
may succumb four to eight weeks after a single intake of toxic plant material,
even though under natural conditions, animals usually consume toxic material
daily over a period of time until they die (Theiler, Du Toit & Mitchell 1923).
Animals typically drop dead without premonitory signs and death is usually
precipitated by exercise. In a minority of cases symptoms consistent with
congestive heart failure can be observed, including weakness, lagging behind
the flock, staggering, gasping for breath and dyspnoea (Kellerman et al. 2005).
Pachystigma pygmaeum (North-West Province and Gauteng) is the most
important of these plants, followed in descending order of importance by
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A study of the pathology and pathogenesis of myocardial lesions in gousiekte, a cardiotoxicosis of ruminants
Fadogia homblei (central Limpopo Province, Gauteng, the north-western part of
Mpumalanga), Pavetta harborii (Limpopo Province), Pachystigma thamnus
(KwaZulu-Natal), Pavetta schumanniana (Mpumalanga and Limpopo Province)
and Pachystigma latifolium (Mpumalanga and KwaZulu-Natal) (Kellerman,
Naudé & Fourie 1995). The wild date, F. homblei, apparently causes stock
losses mostly in early summer, and P. pygmaeum later in the season, while P.
harborii and P. schumanniana are associated with gousiekte throughout the
year (Theiler, Du Toit & Mitchell 1923; Kellerman et al. 2005; Fourie et al.
1994).
In 1995/96, the expected annual impact of mortalities from gousiekte on the
livestock industry in South Africa was estimated at approximately R2,3 million in
the case of cattle and R1 million in the case of small stock (Kellerman, Naudé &
Fourie 1995). Based on the cattle and small stock numbers cited by Kellerman,
Naudé and Fourie (1995) and a value of R6 000 a head in the case of cattle and
R1 000 a head in the case of small stock, the current (2008) annual impact of
mortalities as a result of gousiekte alone is estimated at approximately
R9 million (cattle) and R5,2 million (small stock). No values are available for the
indirect costs, but these are considerable, particularly as a result of the
temporary or permanent non-utilisation of affected pastures and the diminished
value of land infested with toxic plants.
OBJECTIVES OF THIS STUDY
1 To investigate the effect of the duration of latency on the nature of the
myocardial lesions in the left free ventricular wall in sheep dosed with P.
pygmaeum.
2 To characterise microscopical lesion patterns in animals with short and
with medium to long latent periods. The latent period is defined as the
time that elapses between first exposure of the animal to toxic plant
material and death of the animal.
3 To describe the full spectrum of lesions of gousiekte in sheep so that
even “atypical” cases can be diagnosed accurately.
4 To study the pathogenesis of the myocardial lesions in sheep exposed to
plants associated with gousiekte and rats injected with pavetamine.
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A study of the pathology and pathogenesis of myocardial lesions in
gousiekte, a cardiotoxicosis of ruminants
CHAPTER 2
LITERATURE REVIEW
2.1 THE DIFFERENT PLANTS THAT CAUSE GOUSIEKTE
2.1.1 Pachystigma pygmaeum (Schltr.) Robyns (Rubiaceae) (figs 2.1, 2.2)
Also known as the hairy gousiektebossie, Pachystigma pygmaeum is a lowgrowing shrublet with an extensive underground system of stems and roots (fig.
2.1). It occurs mainly in the North-West Province and Gauteng but may also be
found in the northern parts of the Free State, Limpopo Province, Mpumalanga
and KwaZulu-Natal. The broadly elliptical leaves arise from the stem in opposite
pairs and are covered in yellowish hairs. The mature fruit resembles a green
tomato (fig. 2.2).
P. pygmaeum frequently occurs in open grassland in high-lying areas and
remains dormant in the ground during the dry winter months. In early spring,
after the first rain, the gousiektebossie sprouts before the grass. The green
young shoots are very attractive to animals that have been starved of greenery
during the winter and deaths usually occur in the latter half of the summer
(Vahrmeijer 1981; Kellerman et al. 2005).
Theiler (1906–1907) and Walker (1908–1909) reported the first outbreaks of
gousiekte. Sir Arnold Theiler confirmed, by means of a field trial and subsequent dosing trials on the farm Witfontein near Kempton Park, that Vangueria
pygmaeum (now P. pygmaeum) was the cause of the disease.
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A study of the pathology and pathogenesis of myocardial lesions in gousiekte, a cardiotoxicosis of ruminants
Figure 2.1
Pachystigma pygmaeum is a low-growing shrublet
Figure 2.2
The fruits of P. pygmaeum resemble a green tomato
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A study of the pathology and pathogenesis of myocardial lesions in gousiekte, a cardiotoxicosis of ruminants
2.1.2 Pachystigma thamnus Robyns (Rubiaceae) (figs 2.3, 2.4)
Pachystigma thamnus resembles P. pygmaeum except that the former is
smooth leaved and occurs mainly in KwaZulu-Natal and Mpumalanga. The
suspected toxicity of this plant (Steyn 1949; Codd & Voorendyk 1966) was
confirmed by Adelaar and Terblanche (1967).
Figure 2.3
Pachystigma thamnus is smooth leaved
Figure 2.4
P. thamnus. Note the smooth leaves and mature fruit
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A study of the pathology and pathogenesis of myocardial lesions in gousiekte, a cardiotoxicosis of ruminants
2.1.3 Pachystigma latifolium Sond (Rubiaceae) (fig. 2.5)
Pachystigma latifolium is an underground shrub with massive woody axes. The
plant grows approximately 0,5 m tall and the glabrous leaves have short
petioles. The large green fruit ripens to dark-brown or black. P. latifolium occurs
on open and rocky grassland, grassy banks of streams and on coastal sand
flats. It is the only plant known to cause gousiekte near the coast (Kellerman et
al. 2005)
Figure 2.5 Pachystigma latifolium is an underground shrub with massive
woody axes
2.1.4 Fadogia homblei (= F. monticola) De Wild (Rubiaceae) (figs 2.6, 2.7)
Fadogia homblei (wild date) has a perennial taproot with subterranean branches
from which aerial stems grow. These are squarish in cross-section and 300–
500 mm in height. The leaves have a characteristic dark green, shiny upper
surface and a greyish-white, felted lower surface (fig. 2.6). Small, yellowish,
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A study of the pathology and pathogenesis of myocardial lesions in gousiekte, a cardiotoxicosis of ruminants
star-shaped flowers form in the axils of the leaves. The round fruits are peasized and blacken with age (fig. 2.7). F. homblei occurs in central Limpopo
Province, Gauteng and the north-western part of Mpumalanga. Hurter et al.
(1972) investigated outbreaks of gousiekte in the Vaalwater area of Limpopo
Province and identified F. homblei as a cause of the disease.
Figure 2.6 Fadogia homblei. The leaves have a dark green, shiny upper
surface and a greyish-white, felted lower surface
Figure 2.7
with age
F. homblei. The round fruits are pea-sized and blacken
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A study of the pathology and pathogenesis of myocardial lesions in gousiekte, a cardiotoxicosis of ruminants
2.1.5 Pavetta harborii S. Moore (Rubiaceae) (figs 2.8, 2.9)
Pavetta harborii is a perennial, woody shrublet about 50 cm in height, with
subterranean branches that give rise to groups of aerial stems (fig. 2.8). The
plant occurs in Limpopo Province and Botswana and one plant can cover an
area of approximately 2 m in diameter. Opaque bacterial spots may be visible
when the leaves are held up against the light (Van Wyk et al. 1990). A
characteristic feature of the plant is the clusters of white, scented, tubular
flowers with star-shaped corolla lobes and protruding styles that appear in early
summer on the previous season’s growth (fig. 2.9). The fruits are pea sized and
become shiny black with age (Kellerman et al. 2005).
The discovery of P. harborii as a cause of gousiekte resulted from the periodic
occurrence of gousiekte in an area where P. pygmaeum did not occur. Uys and
Adelaar (1957) proved that P. harborii caused the disease by feeding the plant
to cattle and sheep following heavy stock losses on a farm north-west of
Gauteng.
Figure 2.8
Pavetta harborii is a perennial, woody shrublet about 50 cm in
height
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A study of the pathology and pathogenesis of myocardial lesions in gousiekte, a cardiotoxicosis of ruminants
Figure 2.9 P. harborii. Note the cluster of white, tubular flowers with
star-shaped corolla lobes
2.1.6
Pavetta schumanniana F. Hoffm. (Rubiaceae) (figs 2.10, 2.11)
Pavetta schumanniana is a deciduous, multi-branched shrub or small tree up to
4 m in height, with dark-brown, furrowed bark (fig. 2.10). The yellowish-green,
leathery leaves have a rough upper surface and a hairy lower surface and are
conspicuously net veined and covered with dots. The small, white flowers are
borne in clusters at the ends of short branchlets, in the axils of fallen leaves on
the previous year’s growth (fig. 2.11). When mature, the fruits are small and
black. P. schumanniana occurs mostly in Limpopo Province and favours rocky
places (Kellerman et al. 2005; Kellerman, Naudé & Fourie 1995). Naudé, Smit
and Adelaar (Onderstepoort Veterinary Institute, unpublished data 1962)
reproduced the disease experimentally by feeding the plant to sheep.
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A study of the pathology and pathogenesis of myocardial lesions in gousiekte, a cardiotoxicosis of ruminants
Figure 2.10
Pavetta schumanniana is a deciduous, multi-branched shrub
Figure 2.11 P. schumanniana. Small, white flowers are borne in clusters
at the ends of short branchlets
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A study of the pathology and pathogenesis of myocardial lesions in gousiekte, a cardiotoxicosis of ruminants
2.2 CLINICAL SIGNS
Gousiekte in ruminants is characterised by heart failure four to eight weeks after
ingestion of certain rubiaceous plants (Theiler, Du Toit & Mitchell 1923;
Newsholme & Coetzer 1984; Kellerman et al. 2005). The majority of animals
with gousiekte drop dead without showing clinical signs of congestive heart
failure. However, a few animals may show lethargy, weakness, lagging behind
the flock, staggering, respiratory distress, dyspnoea and tachycardia a few days
prior to death (Walker 1908–1909; Theiler, Du Toit & Mitchell 1923; Pretorius &
Terblanche 1967; Pretorius et al. 1973). In an unusual outbreak of gousiekte in
Île-de-France sheep, many animals showed signs of congestive heart failure,
such as respiratory distress and oedema, mainly of the head (Prozesky et al.
1988).
Death can occur spontaneously or can be precipitated by exercise or other
forms of stress, such as handling of the animals (Kellerman et al. 2005). During
a field outbreak of gousiekte near Potchefstroom in North-West Province,
electrocardiograph (ECG) recordings were performed on approximately ten out
of a flock of seventy adult sheep. The animals were kraaled and released after
the ECG recordings. Six of the animals dropped dead within 200 m of the kraal
without
showing
any
premonitory
signs
of
congestive
heart
failure.
Macroscopically, early signs of congestive heart failure, for example
accumulation of fluid in body cavities and mild to moderate lung oedema, were
present. Microscopical lesions characteristic of gousiekte (vide infra) were also
noted. The ECG recordings of the affected animals did not reveal any
abnormalities prior to death (L. Prozesky, University of Pretoria, unpublished
data 1988). According to Pretorius et al. (1973), sino-atrial node (SA node)
arrhythmias were recorded in 56 % of animals exposed to P. pygmaeum. They
speculated that cardiac dilatation, which is often associated with gousiekte,
causes a gallop rhythm, bundle branch block and an increase in P wave
duration.
Pretorius and Terblanche (1967) studied the clinical signs and cardiodynamics
in 50 experimentally induced cases of gousiekte (using P. pygmaeum) in sheep
and goats. They reported that after ingestion of plant material there was a
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A study of the pathology and pathogenesis of myocardial lesions in gousiekte, a cardiotoxicosis of ruminants
considerable variation in the time before cardiac abnormalities could be
detected by auscultation. Furthermore, not all the abnormalities manifested in
all the animals, and the signs occurred in various combinations. Most clinical
signs only occurred during the last two weeks before death, and in 10 % of
animals no signs could be detected before death (table 2.1).
Table 2.1 Clinical signs observed in experimentally induced gousiekte
(using P. pygmaeum) in 50 sheep and goats (Pretorius & Terblanche 1967)
Animals showing
clinical signs
(%)
Longest period prior to
death on which clinical
signs were noted
(days)
Dyspnoea
24
1,5
Tachycardia
86
6
Gallop rhythm
48
7
Hyperpnoea
72
10
Split first heart sound
66
10
Systolic murmur
66
11
Arrhythmia
56
11
Dull first heart sound
50
27
Clinical sign
2.3 MACROSCOPICAL LESIONS
Most animals that die of gousiekte show signs of congestive, mild to severe
heart failure, including generalised congestion, ascites, hydropericardium,
hydrothorax and pulmonary oedema (Theiler, Du Toit & Mitchell 1923;
Newsholme & Coetzer 1984; Kellerman et al. 2005; Prozesky et al. 1988).
According to Theiler, Du Toit and Mitchell (1923) dilatation of both ventricles
and thinning of the free ventricular walls were present in the majority of affected
animals. Other workers claim that more frequently the hearts of animals that
succumb to the disease are normal in size and the ventricular walls are thin and
of a tough consistency (Newsholme & Coetzer 1984).
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A study of the pathology and pathogenesis of myocardial lesions in gousiekte, a cardiotoxicosis of ruminants
2.4 LIGHT-MICROSCOPICAL LESIONS
A diagnosis of gousiekte is usually based on the presence of characteristic
microscopical lesions in the myocardium, namely foci of myofibre necrosis that
vary in size, with replacement fibrosis and lymphocytic infiltrates of varying
intensity, especially in the subendocardial region of the apex and the left free
ventricular wall (Theiler, Du Toit & Mitchell 1923; Newsholme & Coetzer 1984;
Kellerman et al. 2005), and focal or diffuse atrophy of fibres (Prozesky et al.
1988).
Various researchers reported marked deviations from the “typical” lesions that
characterise a histological diagnosis of gousiekte. Smit (1959) reported
degeneration of myofibres as the principal lesion in some naturally poisoned
animals. Hurter et al. (1972) described multifocal degeneration of myocardial
fibres as the most significant lesion in experimental cases. Mortalities were
reported in animals without notable lesions during dosing trials by Adelaar,
Terblanche and Smit (1966). They attributed these more acute lesions to the
high dosage of plant material administered to the animals.
Even though the myocardial lesions associated with gousiekte are well
described, little information is available on the chronological development, and
consequently on the pathogenesis of the lesions. A study of the development of
the lesions is complicated by the fact that acute, subacute and chronic lesions
may be present in the same animal.
There appears to be a close similarity in the pattern of the myocardial lesions in
the majority of animals that die naturally of gousiekte and that in humans
suffering from dilated cardiomyopathy. The latter is regarded as a syndrome in
which a variety of aetiological factors, such as viral infections, toxic agents,
chronic alcohol abuse and genetic factors, have been implicated (Unverferth
1985; Weekes et al. 1999).
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A study of the pathology and pathogenesis of myocardial lesions in gousiekte, a cardiotoxicosis of ruminants
2.5 TRANSMISSION ELECTRON MICROSCOPICAL LESIONS
Transmission electron microscopical lesions reported in experimentally induced
gousiekte in sheep fed P. pygmaeum included a lack of register between
sarcomeres of adjacent myofibrils and disintegration and necrosis of myofibrils.
The disintegration of myofibrils was attributed to a loss of myosin rather than
actin (Schutte et al. 1984).
2.6 PATHOPHYSIOLOGY
Pretorius and Terblanche (1967) suggested that the primary lesion in gousiekte
may be inhibition of the contractile mechanisms of the myocardium, induced by
the toxic principle in gousiekte plants. Snyman, Van der Walt and Pretorius
(1982a) showed that the myocardial lesions in gousiekte are characterised by
impaired energy utilisation in the contractile system and a depression of the
natural actomyosin (n-actomyosin) ATP-ase activity ratio with reduced
sensitivity to activating calcium ions. The same authors also demonstrated a
significant reduction in ATP and creatine phosphate levels in the myocardial
tissue of sheep with gousiekte. They furthermore postulated that the imbalances
in energy production and utilisation along with impaired oxygen uptake by the
mitochondria may be primary or secondary in the pathogenesis of heart failure
associated with gousiekte.
To study the cardiodynamics of gousiekte, the cardiac pulmonary flow index
(CPFI) was used. The CPFI can be defined as the ratio of the cardiopulmonary
blood volume to stroke volume, and is equivalent to the number of heartbeats
necessary to pump blood from the right side to the left side of the heart through
the lungs. The CPFI is obtained by measuring the flow of technetium-labelled
erythrocytes through the right and left ventricles using a sodium iodide crystal
and collimator system (Van der Walt & Van Rooyen 1977; Van der Walt et al.
1981).
An increase in the CPFI is attributed to a decrease in both the stroke volume
and the pumping efficiency of the left ventricle relative to the right ventricle,
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A study of the pathology and pathogenesis of myocardial lesions in gousiekte, a cardiotoxicosis of ruminants
resulting in an increase in the ventricular filling pressure (volume overload) and
pulmonary blood volume (Pretorius et al. 1973; Van der Walt & Van Rooyen
1977; Van Rooyen et al. 1984). An increase in the CPFI (Van der Walt & Van
Rooyen 1977; Fourie et al. 1989), serum aspartate transaminase (AST) activity
(Fourie et al. 1989; Fourie 1994) and tachycardia are reliable clinical and
pathophysiological indicators of cardiac damage in sheep with gousiekte (Van
der Walt & Van Rooyen 1977; Van der Walt et al. 1981; Fourie et al. 1989).
2.7
TOXIC PRINCIPLE IN GOUSIEKTE PLANTS
Numerous attempts over a period of 30 years failed to isolate the toxic principle
of gousiekte plants. The main reasons were the presence of a latent period of
approximately six weeks and the variation in toxicity of the plants (Fourie et al.
1995). The active principle in plants inducing gousiekte was however eventually
isolated (Fourie 1994) and identified as pavetamine (R. Vleggaar, University of
Pretoria, unpublished data 1997).
Fractions were tested in sheep and goats and the induction of gousiekte was
confirmed on the basis of cardiac failure and microscopically detectable
myocardial lesions (Van der Walt & Van Rooyen 1977; Van der Walt et al. 1981;
Fourie et al. 1995). As a result of these studies, rubiaceous plants can now be
assayed chemically to determine their toxicity.
The following characteristics of pavetamine were identified:
•
It is water soluble.
•
It is relatively heat stable.
•
It passes through a dialysis membrane.
•
It has cationic properties.
•
It stains orange when sprayed with ninhydrin on TLC plates.
•
It is pH labile.
Pavetamine is a polyamine. Polyamines are a group of biologically highly active
substances that affect numerous body functions, including cell growth and the
synthesis of new myocardial protein. The inhibition of myocardial protein
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A study of the pathology and pathogenesis of myocardial lesions in gousiekte, a cardiotoxicosis of ruminants
synthesis by pavetamine may play a significant role in the chronological
development of the myocardial lesions of affected animals (Schultz et al. 2001).
2.8 PAVETTA HARBORII AND PAVETAMINE AS A CARDIOTOXIN IN RATS
An alcohol extract of P. harborii was reconstituted and administered
subcutaneously to rats to study various cardiodynamic parameters (Pipedi
1999). The results showed a significantly lower myocardial contractile strength
and left ventricular systolic pressure in the affected animals, confirming that the
P. harborii alcohol extract induced left heart failure in rats.
Macroscopical lesions included mild to moderate oedema of the lungs in rats
necropsied six days after administration of pavetamine. No macroscopical or
light-microscopical lesions were noted in the hearts of the experimental animals,
but transmission electron microscopical studies revealed mild lesions, including
focal areas of myofibrillar lysis and thickening of the Z bands (Pipedi, 1999).
Furthermore, pavetamine inhibited protein synthesis in rat hearts (Schultz et al.
2001). Ellis, Schultz and Basson (2007) studied mechanisms of cardiac gene
expression in rats following pavetamine intoxication, and according to Hay,
Schultz and Schutte (2008), pavetamine significantly reduced systolic function
in experimental rats.
Subtractive-suppressive hybridisation (SSH), a technique used to identify
differentially expressed genes between two populations (Diatchenko et al.
1996), and micro-array analysis, used to study gene expression of the entire
genome of an organism, were used to investigate the mechanism of action of
pavetamine on the hearts of rats (Ellis, Schultz & Basson 2007). Immunolabelling of myosin revealed an altered expression of myosin whereas the
expression of actin remained unaltered. Heart failure in mammals is
characterised by a down-regulation of the alpha isoform and up-regulation of
the beta isoform of cardiac protein genes (Sucharov et al. 2004). Intoxication
with pavetamine gave rise to expression of the beta isoform resulting in a
slower contraction and saving of energy. The myosin light chain is the main
regulatory protein in muscle contraction and consists of two subfamilies, viz. the
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A study of the pathology and pathogenesis of myocardial lesions in gousiekte, a cardiotoxicosis of ruminants
essential light chain and the regulatory light chain (Yamashita et al. 2003). In
pavetamine intoxication down-regulation of the myosin light chain 2 gene results
in impaired contractility of the heart. Furthermore, pavetamine intoxication
resulted in increased expression of the four-and-a-half LIM domain proteins
(Ellis, Schultz & Basson 2007). The latter proteins are also up-regulated in
cases of hypertrophic cardiomyopathy (Lim, Roberts & Marian 2001).
2.9 HEART FAILURE
Heart failure is an important aspect of gousiekte and central to the
pathophysiology of the disease. The tremendous variation in the extent of the
myocardial lesions associated with gousiekte and other cardiotoxic plants
underpins one of the major problems in studying cardiac pathology, viz. the
assessment of the functional significance of lesions.
On the one hand, lesions that appear severe may be clinically silent, whereas
relatively mild lesions may be associated with severe cardiac dysfunction,
arrhythmias and death. Acute lesions that may be difficult to detect may also be
responsible for severe cardiac dysfunction and death. This is well illustrated in
the case of Dichapetalum cymosum (gifblaar) and Moraea spp. (tulp) poisoning
in cattle and sheep (Kellerman et al. 2005).
Another problem in investigating cardiac pathology is the evaluation of chronic
lesions where scar tissue is all that remains, providing no clue to the aetiology
or pathogenesis of the insult. The picture is complicated further by the ongoing,
active nature of myocardial reaction patterns in which acute, subacute and
chronic processes may overlap, as is the case in most animals that succumb
naturally to gousiekte. Even though the initiaI causes of heart failure in man and
in animals with gousiekte differ, most of the anatomical and cardiodynamic
changes are similar (Pipedi 1999).
Two types of heart failure are most frequently recognised, namely acute heart
failure and congestive heart failure. Both types have been reported in animals
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A study of the pathology and pathogenesis of myocardial lesions in gousiekte, a cardiotoxicosis of ruminants
that succumb to gousiekte following an incubation period of four to eight weeks
(Theiler, Du Toit & Mitchell 1923).
2.9.1 Acute heart failure
Acute heart failure is characterised by a sudden loss of consciousness, falling
with or without convulsions, severe pallor of the mucosae and either death or
recovery. Dichapetalum cymosum (gifblaar) is an example of a plant that
causes sudden death in ruminants owing to acute heart failure. The toxic
principle, monofluoroacetate (Marais 1944) is absorbed and converted to
monofluorocitrate that blocks the tricarboxylic acid cycle by inhibiting aconitase.
Affected animals usually drop dead after drinking water or if exerted.
Macroscopically and microscopically there is very little or no morphological
evidence of damage to the heart (Kellerman et al. 2005).
2.9.2 Congestive heart failure
The term congestive heart failure denotes a condition in which the heart is
unable to meet the haemodynamic demands of the body, all compensatory
mechanisms have been exhausted, and the characteristic clinical and
pathological signs, particularly expansion of the extracellular fluid volume and
oedema, are present. The terms left-sided and right-sided heart failure refer to
the failure of the left or the right ventricular capacity to meet the body’s needs
and involve the pulmonary circulation and the systemic circulation, respectively.
Irrespective of the cause, conditions that result in heart failure can be divided
into those that –
•
impose a sustained pressure overload on one or both ventricles;
•
institute a sustained volume overload on one or both ventricles;
•
alter normal contractility of myocardial fibres or result in loss or
replacement of cardiac muscle; or
•
alter the heart’s normal rate and rhythm (Kumar, Cotran & Robbins
2003).
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A study of the pathology and pathogenesis of myocardial lesions in gousiekte, a cardiotoxicosis of ruminants
When myocardial contractibility is disturbed, there is a limited set of
compensatory responses by the body to increase cardiac output. These are
referred to as intrinsic and systemic responses, respectively. Intrinsic responses
include the Frank Starling mechanism of increased preload to control ventricular
performance (ventricular dilatation), and ventricular hypertrophy. Systemic
responses include an increase in heart rate and peripheral resistance,
redistribution of blood flow, venular constriction and an increase in blood
volume (Jubb, Kennedy & Palmer 1993; Braunwald 1992; Kumar, Cotran &
Robbins 2003).
2.9.3 Intrinsic cardiac responses to reduced cardiac output
The morphological changes that represent the intrinsic responses to a reduced
cardiac output are presented in cases of cardiomyopathy irrespective of the
aetiology. Cardiomyopathy is a general diagnostic term designating primary
myocardial disease that can be attributed to various causes.
The subdivision of cardiomyopathies is controversial and can be confounding.
For example, some authors distinguish between concentric and eccentric
hypertrophic cardiomyopathy (Jubb, Kennedy & Palmer 1993) whereas others
refer only to hypertrophic cardiomyopathy (Kumar, Cotran & Robbins 2003).
This is confusing because the criteria used to distinguish between dilated and
eccentric hypertrophic cardiomyopathy are unclear. Restrictive cardiomyopathy
is a form of cardiomyopathy seen mainly in humans. It was included in this
study owing to the resemblance of the myocardial lesions in advanced cases
(subendocardial fibrosis) to those often seen in more chronic cases of
gousiekte.
It was therefore decided to resort to the subdivision of cardiomyopathies into
three major clinicopathological groups, viz. dilated, hypertrophic and restrictive
cardiomyopathy, as outlined by Kumar, Cotran and Robbins (2003).
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A study of the pathology and pathogenesis of myocardial lesions in gousiekte, a cardiotoxicosis of ruminants
2.9.3.1 Dilated cardiomyopathy
Macroscopically the dilated heart is enlarged and flabby and has a rounded
shape with thinning of the free wall of the dilated chamber. Microscopically the
myocardial lesions are non-specific and are characterised by varying degrees of
myocyte degeneration, necrosis, atrophy and hypertrophy with multifocal
interstitial fibrosis and a mononuclear inflammatory infiltrate (Jubb, Kennedy &
Palmer 1993; Bastianello et al. 1995; Kumar, Cotran & Robbins 2003).
Dilated cardiomyopathy that varies in extent is often seen in natural cases of
gousiekte (Theiler, Du Toit & Mitchell 1923). Dilated cardiomyopathy is a
syndrome in which a variety of aetiological factors in man and animals, such as
viral infections, toxic agents (e.g. cobalt), chemotherapeutic agents (including
doxorubicin) (Kumar, Cotran & Robbins 2003), ionophore intoxication (Bastianello et al. 1995), chronic alcohol abuse, genetics and tachycardia, give rise
to a common cardiac dysfunction (Unverferth 1985; Weekes et al. 1999; Byrne
et al. 2002). Furthermore, a variety of circumstantial evidence suggests that
dilated cardiomyopathy can result directly from myocarditis (Pisani, Taylor &
Mason 1997; Kumar, Cotran & Robbins 2003).
In bovine hereditary dilated cardiomyopathy a number of myocardial proteins
are significantly reduced (Weekes et al. 1999; Furuoka et al. 2001). Many of
these proteins are found exclusively in the mitochondria, suggesting that in this
case the myocardium is unable to provide sufficient energy to cope with the
increased workload and mechanical stresses associated with the rearrangement of the muscle fibres.
Dilated cardiomyopathy in humans and animals may be a pathological or a
physiological response, for example the requirements of improved performance
in racehorses. When it is the result of a pathological condition it is characterised
by impaired systolic function with a reduced ejection fraction and increased
preload (volume overload) since the heart adapts to maintain a normal stroke
volume (Dec & Fuster 1994; Weekes et al. 1999). When the dilated cardiomyopathy is a physiological response, an increase in the preload will increase
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A study of the pathology and pathogenesis of myocardial lesions in gousiekte, a cardiotoxicosis of ruminants
the contractile force of the heart, which, within certain limits, results in an
increase in the stroke volume (Braunwald 1992; Guyton & Hall 2000).
2.9.3.2 Hypertrophic cardiomyopathy
Cardiac hypertrophy, also referred to as hypertrophic cardiomyopathy, is
characterised by a reversible increase in the mass and wall thickness of the
affected chamber and an increase in the size of the papillary muscles and the
trabeculae carneae. Cardiac hypertrophy is a compensatory response, both
physiologically and pathologically, to increased systolic or diastolic workload
(pressure overload) and mostly affects the ventricles and the interventricular
septum (Jubb, Kennedy & Palmer 1993; Kumar, Cotran & Robbins 2003;
Guyton & Hall 2000). It has not been reported in animals that succumbed to
gousiekte.
Hypertrophic cardiomyopathy is characterised by powerful contractions that
rapidly expel blood from the ventricles. However, the hypertrophic walls impair
diastolic filling and consequently cardiac output is reduced. Even though the
aetiology is unknown in many cases of hypertrophic cardiomyopathy in humans,
abnormalities in the genes that encode sarcomeric contractile proteins appear
to play an important role in the development of this syndrome. Other causes in
both humans and animals include increased systolic loads as found in aortic
stenosis and pulmonic stenosis, and pulmonary hypertension in patent ductus
arteriosus (Jubb, Kennedy & Palmer 1993; Kumar, Cotran & Robbins 2003;
Cunningham & Klein 2007).
The macro-appearance of an affected heart will depend on the chamber
affected and the nature of the insult. In general, hypertrophy of the right side of
the heart makes the heart broader at its base, hypertrophy of the left side
increases the organ’s length, and bilateral hypertrophy produces a more
rounded shape than normal.
The most characteristic microscopic lesion in hypertrophic cardiomyopathy is a
haphazard arrangement of hypertrophic, abnormally branching myocytes. The
endocardium may be diffusely opaque as a result of fibrosis. The latter
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A study of the pathology and pathogenesis of myocardial lesions in gousiekte, a cardiotoxicosis of ruminants
alteration may be the best indication of hypertrophy in the atria, which may be
difficult to assess macroscopically (Jubb, Kennedy & Palmer 1993; Radostits et
al. 2000; Kumar, Cotran & Robbins 2003).
2.9.3.3 Restrictive cardiomyopathy
Restrictive cardiomyopathy is characterised by a primary decrease in ventricular
function, resulting in reduced ventricular filling during diastole. It is not a
common form of cardiomyopathy in humans and animals, and the most
common cause in man is a condition (disease) referred to as endomyocardial
fibrosis, a disorder of unknown aetiology that accounts for up to 10 % of cases
of childhood heart disease in tropical areas. Apparently, genetic factors account
for some of the cases. Restrictive cardiomyopathy is sometimes associated with
dilated cardiomyopathy.
The atria are usually dilated and the ventricles may be of normal size or dilated,
particularly during the later stages of the disease. The endocardium is thickened
and opaque, and histological features include endocardial fibrosis that may
extend into the underlying myocardium (subendocardial fibrosis), which results
in congestive heart failure (Kumar, Cotran & Robbins 2003).
2.10
HYPOTHESES
•
The myocardial lesions in animals with gousiekte represent a final
common pathway of cellular damage rather than a manifestation of a
specific type of heart disease.
•
Pavetamine affects myocardial protein synthesis but does not
selectively affect myocardial fibres in the subendocardial region. The
predilection for hypertrophy or degeneration of myofibres in the
subendocardial region is related to both the effect of pavetamine and
the diminished perfusion that potentiates the primary myocardial
dysfunction.
•
“Atypical lesions” represent a manifestation of the disease in a
progression that terminates with dilated cardiomyopathy.
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